Laxative compositions and method for making same

ABSTRACT

Pharmaceutical compositions for rectal administration comprising an effervescent mixture comprising sodium bicarbonate and glutamic acid or pyroglutamic acid with at least one diluent adapted for rectal administration, said mixture being effervescent.

The present invention reports to the therapeutic chemistry domain andmore particularly to pharmacotechny.

It is more precisely related to new pharmaceutical compositions withlaxative properties whom the main characteristic is to contain aneffervescent mixture producing fast and gradually carbon dioxide.

The invention specifically reports to new pharmaceutical compositionsdesigned for the rectal route able to producing by a chemical reactionactive principles in contact with humidity existing in the rectal ampulean important and quick gaseous release.

The French patent number 788.198 (Waldenmeyer J. G.) has alreadydescribed a process to obtain effervescent suppositories which offer thepossibility to release native carbon dioxide under action of humidity,heat or any other reason in which the raw materials releasing this acidby their mixing are coated for protection in a greasy substance whichthus avoid a premature chemical reaction and consequently protectagainst decomposition.

Meanwhile these suppositories contain in their bulk, hydrophilicingredients which allow to the biologic fluids to penetrate into thebulk and allow the start of the chemical reaction which involves thephysiologic effect.

Later on the French patent application number 94.11913 filled on Oct. 5,1994 by the Applicant has described a new process to manufacture sucheffervescent suppositories on a potassium tartrate acid and sodiumbicarbonate basis, stable during preservation.

The problem which occurred for the realization of suppositoriesdescribed in the previous literature has been to be able to form asufficiently effervescent bulk, i.e. to release a sufficiently importantvolume of carbonic gas in a sufficiently reduced set of time to obtain amarked distension of coasts of the rectal ampoule, which produce arelieving reflex.

Different solutions exist to try to solve this problem. The firstsolution consists to enhance the amount of reactive active principles toincrease the released volume of carbonic gas. Meanwhile the size of asuppository rapidly reaches a limit and so it is not possible toincorporate more active ingredients without changing the conservationand homogeneity of the suppositories.

The other solution consists to incorporate into the mass of thepharmaceutical composition intended to the rectal route, another acidcomponent more reactive than potassium acid tartrate and offering allthe required guarantees about local tolerance and lack of toxicologicalrisk whom the limit remains in the necessity to do not generate a toocoarse release of carbon dioxide.

This solution lies as a basis for the invention which is the subject ofthe present application.

Therefore the invention consists in pharmaceutical compositions intendedto the rectal route, formed with an effervescent mixture consisting ofan alkali-metal bicarbonate and a determined acid reactive compound,selected in the group formed by monosodium or monopotassium phosphate,monosodium citrate, pyroglutamic acid and glutamic acid, associated oradmixed with one or more diluents or vehicles adapted to the realizationof a pharmaceutical form intended to the rectal route.

The effervescent formulation calls for the presence of an alkalineelement liable to release easily carbonic gas by a chemical reactionwith an acid compound. The experiment shows that with alkaline oralkaline earth metal or others metals carbonates, the reaction is muchslower and rarely complete in a relatively short set of time. By anotherway the selection of the acid compound needs to take considerations oftwo conditions. This acid compound must not be irritant or toxic on theone hand, and does not launch a too violent or fast effervescentreaction in contact with the alkaline agent. There are only a limitednumber of acid compounds which satisfy to these both conditions. Amongthe factors which can involve for the respect of these conditions, thereis firstly the pka of the used acid compound and on the other hand thesolubility of the acid compound in water or in the biologicalenvironment. Thus, a compound like benzoic phtalimide or succinimide dueto their low solubility in water only induces a reduced and delayedrelease. It is also possible that their low degree of acidity play somepart.

At the contrary the incorporation in the mixture of strong acidcompounds or very soluble acids in aqueous mediums lead to a very strongor too fast gaseous release which exclude the use of such compounds.

Thus, it is not possible to use any acid compound if it does not fallinto the category defined above and this fact requires a preliminaryadjustment to determine whether the acidic compound is suitable for sucha use.

About pharmaceutical compositions intended to the rectal usesuppositories made with a synthetic or natural greasy matrix areindicated firstly, and also rectal capsules realized with gelatine.Others solid or coated forms of administration by rectal route, can alsobe considered.

According to the needs, the acid compound content will be that whichalso approximately agrees on the molar level with the formulationdefined in the previous application in France number 94.11913 by theapplicant, namely 1.150 g potassium acid tartrate with 0.700 g ofbicarbonate sodium for an adult suppository, i.e. preferably between1.15 g and 1.20 g, 1.184 g for monosodium phosphate, between 1.25 and1.30 g and preferably 1.2847 g for monosodium citrate, or for a diacidsubstance as glutamic acid, between 0.85 and 0.90 g and preferably 0.878g and for pyroglutamic acid between 0.85 and 0.90 g and preferably 0.889g. Under these conditions the mixture is able to release a measuredvolume of CO₂ determined with the Bernard's calcimeter, underatmospheric pressure, about 100 to 120 ml for a suppository during 20minutes.

The study of the carbonic gas release shows that during the first fiveminutes a maximal gaseous release occurred which represents about 80% ofthe total release. Then the release slows down to reach an asymptomaticvalue after 10 minutes, and after 20 minutes the variations of volumebecome very small. Depending on the nature of the acid agent, thisgaseous release can be very fast and nearly complete after 5 minutes oron the contrary remaining small and needing more than 40 minutes toreach its achievement. Therefore, it is between these two utmost valuesthat the therapeutic optimum takes place.

This invention is also related to a process of realization ofpharmaceutical compositions intended for the rectal route, which consistto blend an acid reactive salt selected among monosodium phosphate,monopotassium phosphate, monosodium citrate, pyroglutamic acid andglutamic acid and an alkali-metal bicarbonate with an hydrophilicexcipient then to an opacifiant agent and this mixture is introduced ina fusible greasy excipient near the body temperature.

In a particular mode of realization, the hydrophilic excipient ispreferably an animal or vegetable lecithin, as for example Soya lecithinor yolk lecithins.

The opacifiant agent is a mineral product, in a powder form, insolublein the hydrophilic excipient and in the greasy excipient. The opacifiantagent will be preferably an aluminium silicate, a magnesium silicate, atitan oxide or silica.

The greasy excipient is a grease with a melting point lying around 40°C., like cocoa-butter, shea butter, Bassia longifolia (Oleum bassiae)butter or mixtures of them or a polyacohol stearate like asemi-synthetic or synthetic polyethyleneglycol or glyceryl stearate, themelting point of which is situated in this temperature range likepolyethyleneglycol stearate commercialised under the denomination TradeName LABRAFIL and semi-synthetic glycerids described in the FrenchPharmacopea 10^(th) edition and commercialised under the appellationTrade Name SUPPOCIRE® . . .

Considering rectal capsules, greasy excipient is not used or only insmall amounts to secure an homogeneous solid bulk. This preparation isintroduced into a gelatine capsule the thickness of which varies from 1to 3 mm.

The following examples illustrate the main characteristics of theinvention without limiting them.

Effervescence Measure by Release of CO₂

Working of the Bernard's calcimeter.

The assay consists in verifying the working of the equipment of theBernard's calcimeter.

Material

a 500 ml flask

a graduated tube until 200 ml

a glass tube

a 250 ml flat-bottomed flask, with an inclined lateral neck, at 30° C.

a rubber stopper perforated by a hole for the neck of the flask

a full rubber stopper for the lateral neck supporting a capsule forpowders and suppositories

a magnetic heating stirrer

a saturated sodium chloride solution

Modification

A little modification has been made on the rubber stopper of the lateralneck by adding a tap. This addition is necessary until at time 0, theexperiment begins with an inner pressure equal to the atmosphericpressure.

Installation

Hang the flask and the graduated tube to a support

Connect the flask and the bottom of the graduated tube with a pipe,allowing the connection of the saturated Na chloride solution betweenthe two installations

Connect the top of the graduated tube and the reaction flask with aglass tube across which the CO₂ rises from the flask

Mode of Operation

Introduce a saturated sodium chloride solution in the flask and thegraduated tube

Adjust the level of the graduated tube before starting the experiment

Lay on the magnetic heating stirrer the flask containing 100 ml ofdistilled water at 37° C.

Fill up the flask with a stopper previously fixed at the end of thereleasing tube of CO₂

Introduce the suppository in the flask without contact occurring betweenthe suppository and the water

Verify again the sodium chloride level in the graduated tube beforeturning off the tap of the side stopper

Turn off the tap

Turn on the stirrer and drop the suppository, without forget to unlockthe chronometer

The experiment takes place at the temperature of the laboratory (about20° C.).

Intensity of the Reaction Between the Basic Compounds

This ASSAY is made on the two basic active principles with respect tothe amounts of each product according to the industrial formula.

Mode of Operation

ASSAY 1 Time (minutes) ml 1  2,5 2 49,2 3 66,8 4 73   5 83,2 6 94,6 7>100   

Weigh exactly the required amounts for the two active principles for onesuppository. Mix manually and make the experiment.

Sodium bicarbonate 0.700 g Potassium acid tartrate 1.150 g

Manufacture of the Suppositories

10 batches have been produced according the industrial protocol andassayed the same day.

The suppositories remain insoluble at the temperature of the laboratory(20° C.) during the study of the release of CO₂. Thus, it is necessaryto heat the water until 37° C. Thus a magnetic heating stirrer has beenused.

The Reference Curve of Two Active Principles at 37° C. has been MadeAgain

Proportions for Suppositories for Adults:

Na bicarbonate 0.700 g

K acid tartrate 1.150 g

number of experiments 5 ASSAY ASSAY ASSAY ASSAY ASSAY AVER- 1 2 3 4 5AGE Time ml ml ml ml ml ml 1 44.2 43 42.6 44.2 44.8 43.76 2 57.8 56.2 5062 61.3 57.46 3 67.2 65.8 63.4 72.6 70.8 67.96 4 73.3 73.2 72.2 79.177.2 75.1 5 78.8 78.6 78.5 84.2 81.8 80.38 6 82.7 82.6 83.4 87.8 85.484.38 7 85.8 85.9 87.3 90.6 88.2 87.56 8 88 88.5 90.2 92.9 90.2 89.96 991.2 90.8 92.3 94.6 92.2 92.22 10 92.2 92.6 94 96.2 93.4 93.68 11 9494.1 95.1 97.4 94.6 95.04 12 95.2 95.2 96.6 98.4 95.6 96.12 13 96.2 96.296.8 99 96.2 96.88 14 96.7 97 97.6 99.6 96.7 97.52 15 97.6 97.8 98.4 10097.2 98.2 16 98.4 98.4 99 100 97.8 98.72 17 99 99 99.4 100 98.1 99.1 1899.6 99.5 99.7 100 98.4 99.44 19 100 99.8 99.8 100 98.4 99.6 20 100 10099.8 100 98.4 99.64 21

Proportions for suppositories for children:

Na bicarbonate 0.350 g

K acid tartrate 0.575 g

number of experiments 3 ASSAY 2 ASSAY 3 ASSAY 4 AVERAGE Time ml ml ml ml 1 16,2 15,4 14,4 15,33  2 25,8 25,4 24,6 25,27  3 32,8 32,8 32,1 32,57 4 37,9 38,2 37,8 37,97  5 42   42,2 41,8 42,00  6 45,1 45   44,8 44,97 7 47,2 47,4 47,2 47,27  8 48,8 49   48,9 48,90  9 49,9 50,4 50,1 50,1310 50,6 51,6 51   51,07 11 51,4 52,7 51,9 52,00 12 52   53,3 52,6 52,6313 52,4 53,6 53   53,00 14 52,6 54   53,4 53,33 15 53   54,4 53,8 53,7316 53   54,6 54   53,87 17 52,3 54,9 54,2 53,80 18 54   55   54,2 54,4019 54,2 55   54,2 54,47 20 54,4 55   54,2 54,53

I—Formulation Study According to the Invention Acid Saccharin

This ASSAY begins by the stoichiometric calculation to determine therequired amount of saccharin to use without changing the amount ofbicarbonate contained in the industrial formula.

Saccharin (C₇H₅O₅NS); 1 mole=183 g→6.10⁻³ mole=1.119 g

it is needed for suppositories for adult 1.119 g of acid saccharin.

it is requested for a suppository for children 1.119:2=0.5595 g of acidsaccharin

Formula: Acid saccharin 0.5595 g Na bicarbonate  0.350 g

Bolt the saccharin before weighting it (bolter 0.315) Results forrelease:

number of experiments 2 ASSAY ASSAY 0,5595 g 0,5595 g AVERAGE Time ml mlml  1 24,00 27,00 25,80  2 28,40 33,40 30,90  3 32,10 37,50 34,80  435,00 40,30 37,65  5 37,40 42,60 40,00  6 39,40 44,40 41,90  7 41,3045,80 43,55  8 42,90 47,00 44,95  9 44,20 48,00 46,10 10 45,40 48,8047,10 11 46,50 49,40 47,95 12 47,40 50,20 48,80 13 48,10 50,80 49,45 1448,80 51,30 50,05 15 49,40 51,50 50,45 16 50,00 51,80 50,90 17 50,4051,90 51,15 18 50,80 52,00 51,40 19 51,20 52,40 51,70 20 51,60 52,4052,00 21 51,80 52,60 52,20

II—Pyroglutamic Acid

Stoichiometric calculation:

Pyroglutamic acid (C₅H₇O₅N); 1 mole=147 g→6.10⁻³ mole=0.899 g

it is needed for a suppository for adult 0.899 g of pyroglutamic acid

it is needed for a suppository for children 0.899 g:2=0.4495 g ofpyroglutamic acid

Formula: Pyroglutamic acid 0.4495 g Na bicarbonate  0.350 g

Reduction of the Amount of Pyroglutamic Acid

Formula: Pyroglutamic acid 0.400 g Na bicarbonate 0.350 g

Conclusion

With pyroglutamic acid (0.4495 g) the same phenomenon as with acidicsaccharin occurs: during the first two minutes the CO₂ release isimportant. With a little weaker pyroglutamic acid rate (0.400 g), thetime for CO₂ release is a little shorter.

III—Crystalline Monopotassium Phosphate

Stoichiometric calculation:

Crystalline. Monopotassium phosphate(PO₄H₂K);1 mole=136.09 g→6.10⁻³mole=0.832 g

It is needed for a suppository for adults 0.832 g of monopotassiumphosphate

It is needed for a suppository for children 0.832 g :2==0.416 g ofmonopotassium phosphate

Formula: Monopotassium phosphate 0.416 g Na bicarbonate 0.350 g

Conclusion

Small CO₂ release.

Use a twofold amount with regard to the stoichiometric calculation.

Results for release:

number of experiments 3 Bicarb. 0,7 g Doses of monopotassium ASSAY ASSAYASSAY phosphate 0,832 g 0,832 g 0,832 g AVERAGE Time ml ml ml ml  1 15,213   12,8 13,67  2 22   19,8 20,4 20,73  3 27,6 25,4 26,5 26,50  4 32,630,1 31,8 31,50  5 36,9 34,2 36,2 35,77  6 40,6 37,7 40   39,43  7 43,940,9 43,4 42,73  8 46,8 43,5 46,1 45,47  9 49,1 45,8 48,6 47,83 10 51,448   50,8 50,07 11 53,3 49,8 52,7 51,93 12 54,8 51,3 54,2 53,43 13 56,252,7 55,7 54,87 14 57,4 54,1 56,9 56,13 15 58,5 55,4 58   57,30 16 59,656,5 58,8 58,30 17 60,4 57,4 59,7 59,17 18 61,1 58,4 60,5 60,00 19 61,859,2 61,1 60,70 20 62,4 59,8 61,6 61,27 21 63   60,3 62,1 61,80 22 63,460,9 62,6 62,30 23 63,8 61,4 63,1 62,77 24 64,3 62   63,4 63,23 25 64,762,4 63,8 63,63 26 65   62,6 64   63,87 27 65,2 62,8 64,3 64,10 28 65,463   64,5 64,30 29 65,5 63,2 64,5 64,40 30 65,6 63,2 64,5 64,43 31 65,863,2 64,5 64,50

IV—Anhydrous Monosodium Phosphate

Stoichiometric calculation:

Anhydrous monosodium phosphate (NaH₂PO₄);1 mole=119.98 g→6.10⁻³mole=0.734 g

It is needed for a suppository for adults 0.734 g of monosodiumphosphate

It is needed for a suppository for children 0.734 g:2=0.366 g ofmonosodium phosphate

Formula: twofold amount with regard to the stoichiometric calculation.

Monosodium phosphate 0.734 g Na bicarbonate 0.700 g

Results of release

number of experiments 3 Bicarb. 0.7 g Screen 0.250 mm MonopotassiumASSAY ASSAY ASSAY Phosphate 0.734 g 0.734 g 0.734 g AVERAGE Time ml mlml ml  1 16.2 16.5 13.6 15.43  2 24.2 24.9 21.2 23.43  3 30.4 31.8 2830.07  4 35.5 37.3 33.8 35.53  5 39.8 41.9 38.6 40.10  6 43.3 45.5 42.243.67  7 46.2 48.8 45.4 46.80  8 48.7 51.3 48.1 49.37  9 50.9 53.6 50.451.63 10 52.7 55.5 52.4 53.53 11 54.2 57.2 54.1 55.17 12 55.6 58.6 55.656.60 13 56.9 59.7 57 57.87 14 58.2 60.9 58 59.03 15 59.2 51.8 59 60.0016 60.2 62.4 59.6 60.73 17 61 63 60.3 61.43 18 61.6 63.4 60.8 61.93 1962.2 63.8 61.2 62.40 20 62.6 64.1 61.6 62.77 21 63.1 64.4 61.9 63.13 2263.4 64.6 62.1 63.37 23 63.8 64.8 62.3 63.63 24 64.2 64.9 62.5 63.87 2564.5 64.9 62.6 64.00 26 64.6 64.9 62.8 64.10 27 64.8 64.9 62.8 64.17 2864.9 64.9 62.8 64.20 29 65 64.9 62.8 64.23

V—Succinimide

Stoichiometric calculation

Succinimide (C₄H₅NO₂);1 mole=99.09 g→6.10⁻³ mole=0.606 g

It is needed for a suppository for adults 0.606 g of Succinimide

It is needed for a suppository for children 0.606 g:2=0.303 g ofSuccinimide

Formula Succinimide 0.303 g Na bicarbonate 0.305 g

Results for release: (see table)

Conclusion

CO₂ release is very small with respect to the specified amounts ofactive principles by the stoichiometric calculation.

NUMBER OF ASSAYS 1 ASSAY 0.303 g Time ml  1 2.0  2 2.6  3 3.1  4 3.4  53.7  6 4.1  7 4.4  8 4.7  9 5.1 10 5.3 11 5.6 12 5.9 13 6.1 14 6.3 156.6 16 6.8 17 7.0 18 7.3 19 7.5 20 7.6 21 7.8 22 7.9 23 8.0 24 8.1 258.2 26 8.3

B-Galenic Assay for Suppositories with Anhydrous Monosodium Phosphate

To have a satisfactory CO₂ release, two-fold of the stoichiometricamount has been to be introduced.

Reference Formula for Children

K acid tartrate 0.575 g Na bicarbonate 0.350 g Soya lecithin 0.105 gTalc 0.0525 g SUPPOCIRE ® 0.9175 g 2.000 g

Use of anhydrous monosodium phosphate instead of K acid tartrate:

Formula: Anhydrous monosodium phosphate 0.734 g Na bicarbonate 0.700 gSoya lecithin 0.105 g Talc 0.0525 g SUPPOCIRE ® 0.4085 g 2.000 g

Calculated for 10 suppositories.

Results

The manufacture of the suppositories has been proved difficult becauseit has been requested to heat until 60° C. to fill up the alveolus onthe one hand and the bulk was too pasty and granular on the other hand.This difficulty can be due to the small amount of SUPPOCIRE® used. TheCO₂ release assay made after 24 hours is indicated in the tablehereafter.

ASSAY ASSAY ASSAY AVERAGE CORRECT 2.3738 g 2,3687 g 2.4 g 2.38083 g 2 gTime ml ml ml ml ml  1 4.5 6 6.2 5.57 4.68  2 23.4 23.2 26.6 24.40 20.50 3 34.8 34.4 40.2 36.47 30.63  4 43.4 42.2 49.4 45.00 37.80  5 49.8 48.556.1 51.47 43.23  6 54.6 52.3 61.1 56.00 47.04  7 58.3 55.2 64.8 59.4349.93  8 61.1 58.2 67.8 62.37 52.39  9 63.2 60.7 69.8 64.57 54.24 10 6563 71.4 66.47 55.84 11 66.3 64.8 72.6 67.90 57.04 12 67.5 66.1 73.669.07 58.02 13 68.4 67.2 74.1 69.90 58.72 14 69.1 68.4 74.8 70.77 59.4515 69.8 69.4 75.4 71.53 60.09 16 70.4 70.3 75.8 72.17 60.62 17 71 71.476.2 72.87 61.21 18 71.6 72.2 76.4 73.40 61.66 19 72 72.8 76.8 73.8762.05 20 72.4 73.3 77 74.23 62.36 21 72.7 73.6 77.2 74.50 62.58 22 72.874 77.2 74.67 62.72 23 72.9 74.3 77.2 74.80 62.84 24 73.2 74.7 77.275.03 63.03 25 73.2 75 77.2 75.13 63.12 26 73.2 75.4 77.2 75.27 63.23 2773.2 75.4 77.2 75.30 63.26 28 73.2 75.7 77.2 75.37 63.31

Conclusion

The comparison of the obtained curves with tartrate plus Na bicarbonateon one hand the NaPO₄H plus Na bicarbonate on the other hand with thecurves of the NaPO₄H and Na bicarbonate suppositories shows that thereis no reaction between the powder and the excipient. The suppositoriesprovide a curve identical to the one of the mixture of powders alone.

number of experiments   3 ASSAY ASSAY AVERAGE TARTRATE HPO4NaSuppository 2 g Time ml ml ml  1 15.33 15.43 4.68  2 25.27 23.43 20.5  332.57 30.07 30.63  4 37.97 35.53 37.8  5 42.00 40.1 43.23  6 44.97 43.6747.04  7 47.27 46.8 49.93  8 48.90 49.37 52.39  9 50.13 51.63 54.24 1051.07 53.53 55.84 11 52.00 55.17 57.04 12 52.63 56.6 58.02 13 53.0057.87 58.72 14 53.33 59.03 59.45 15 53.73 60 60.09 16 53.87 60.73 60.6217 53.80 61.43 61.21 18 54.40 61.93 61.66 19 54.47 62.4 62.05 20 54.5362.77 62.36 21 54.53 63.13 62.58 22 63.37 62.72 23 63.63 62.84 24 63.8763.03 25 64 63.12 26 64.1 63.23 27 64.17 63.26 28 64.2 63.31 29 64.23

Comparison of the Different NaPO4H2 Titrations

The following table shows the regrouped results about the differenttitrations of the anhydrous monosodium phosphate suppositories withregard to the 2 g suppositories obtained by industrial manufacture andto the 2 g suppositories manufactured in the Galen cal laboratory.

PO₄HNa PO₄HNa PO₄HNa PO₄HNa 0.592 g 0.5624 0.497 g 0.367 g Indus- Labor-Labor- Labor- Labor- Labor- trial atory atory atory atory atory averageaverage average average average average Time 2 g 2 g 2 g 2 g 2 g 2 g 00.00 0.00 0.00 0.00 0.00 0.00 1 2.20 3.48 5.88 4.79 3.83 3.63 2 5.209.00 16.79 13.19 9.69 7.04 3 8.61 14.95 22.67 19.24 14.51 10.02 4 11.9720.10 27.52 24.03 18.80 12.62 5 15.21 24.37 31.50 28.20 22.34 14.68 618.24 27.52 35.14 31.46 25.33 16.47 7 20.95 30.39 38.25 34.25 27.2417.99 8 23.51 32.68 41.02 36.79 29.84 19.23 9 25.98 34.59 43.27 38.7931.78 20.26 10 28.18 36.35 45.52 40.48 33.36 21.13 11 30.42 37.78 47.3441.99 34.79 21.89 12 32.55 39.11 48.98 43.34 36.01 22.65 13 34.52 40.3450.54 44.49 37.09 23.19 14 36.29 41.49 51.84 45.40 38.08 23.73 15 38.0242.58 53.14 46.19 38.90 24.06 16 39.56 43.69 54.09 46.88 39.59 24.60 1741.06 44.61 55.04 47.47 40.20 25.14 18 42.39 45.59 55.91 47.97 40.8925.68 19 43.73 46.32 56.60 48.44 41.32 26.12 20 44.86 47.11 57.29 48.8541.78 26.55 21 45.89 47.72 57.81 49.19 42.03 26.87 22 46.79 48.39 58.1649.45 42.29 27.15 23 47.56 49.01 58.42 49.66 42.54 27.42 24 48.26 49.4858.76 49.88 42.72 27.63 25 48.83 50.04 59.20 50.04 42.95 27.85 26 49.4050.53 59.54 50.13 43.05 28.07 27 49.80 50.97 59.71 50.29 43.13 28.28 2850.23 51.40 59.89 50.39 43.23 28.39 29 50.56 51.74 60.41 50.45 43.2328.50 30 50.83 52.10 60.75 50.45 28.61

Preservation Study of the Suppository Preparations with AdultProportions by Ageing at Ambient Temperature (20° C.) in a ThermostatedBath Controlled Hygrometry

Reference Formula

Reference formula manufactured in the Galen cal laboratory:

K acid tartrate 1.150 g Na bicarbonate 0.700 g Soya lecithin 0.210 gTalc 0.105 g SUPPOCIRE ® 1.835 g 4.000 g

Results

Good homogeneity of the batch.

ASSAY 1 ASSAY 2 ASSAY 3 AVERAGE 3.9058 3.9226 3.9246 3.9177 Time ml mlml ml  5 44.5 31.5 42 39.33 10 73 63 72 69.33 20 100.5 96 100.5 99.00 40108.5 110 112.5 110.33

Corrected to 4 g

ASSAY 1 ASSAY 2 ASSAY 3 AVERAGE 4.0000 4.0000 4.0000 4.0000 Time ml mlml ml  5 45.6 32.1 42.8 40.2 10 74.8 64.2 73.4 70.8 20 102.9 97.9 102.4101.1 40 111.1 112.2 114.7 112.6

Compositions According to the Invention

1—With monosodium phosphate

Formula Monosodium phosphate 1.184 g Na bicarbonate 1.128 g Soyalecithin 0.210 g Talc 0.105 g SUPPOCIRE ® 1.373 g 4.000 g

Results

Good bulk homogeneity

ASSAY 1 ASSAY 2 ASSAY 3 AVERAGE 4.6744 4.4121 4.3818 4.4894 Time ml mlml ml  5 71.5 59 64 64.83 10 94 84 85 84.67 20 121 107.5 110 112.83 40134 121.5 126 127.17

Corrected to 4 g

ASSAY 1 ASSAY 2 ASSAY 3 AVERAGE 4.0000 4.0000 4.0000 4.0000 Time ml mlml ml  5 61.2 53.5 58.4 57.7 10 80.4 76.2 77.6 78.1 20 103.5 97.5 100.4100.5 40 114.7 110.2 115.0 113.3

2—With Glutamic acid

Forumla: Glutamic acid 0.878 g Sodium bicarbonate 0.700 g Soya lecithin0.210 g Talc 0.105 g SUPPOCIRE ® 2.107 g 4.000 g

Results

Homogeneous batch.

ASSAY 1 ASSAY 2 AVERAGE 3,5728 3,6235 3,5982 Time ml ml ml  5 58 57,557,75 10 85 81,5 83,25 20   97,5 100   98,75 40 101  102   101,50 

Corrected to 4 g

ASSAY 1 ASSAY 2 AVERAGE 4,0000 4,0000 4,0000 Time ml ml ml  5  64,9 63,5  64,2 10  95,2  90,0  92,6 20 109,2 110,4 109,8 40 113,1 112,6112,8

3—With pyroglutamic acid

Pyroglutamic acid 0.889 g Sodium bicarbonate 0.700 g Soya lecithin 0.210g Talc 0.105 g SUPPOCIRE ® 2.096 g 4.000 g

Results: Homogeneous Bulk

ASSAY 1 ASSAY 2 ASSAY 3 3,7341 3,7351 3,5711 AVERAGE Time ml ml ml3,6801  5  47  55 43  48,33 10  89,5    92,5   81,5  87,83 20   107,5103 97 102,50 40 110 103 100  104,33

Corrected to 4 g

ASSAY 1 ASSAY 2 ASSAY 3 AVERAGE 4,0000 4,0000 4,0000 4,0000 Time ml mlml ml  5  50,3  58,9  48,2  52,5 10  95,9  99,1  91,3  95,4 20 115,2110,3 108,6 111,4 40 117,8 110,3 112,0 113,4

4—with monosodium citrate

Formula: Monosodium citrate 1.2847 g  Sodium bicarbonate 0.700 g Soyalecithin 0.210 g Talc 0.105 g SUPPOCIRE ® 1.7003 g  4.000 g

Results: Homogeneous Bulk.

ASSAY 1 ASSAY 2 AVERAGE 3,9785 4,148 4,0633 Time ml ml ml  5 98  110104,00 10 124   131 127,50 20 142,5 147 144,75 40 149,5 149 149,25

Corrected to 4 g

ASSAY 1 ASSAY 2 AVERAGE 4,0000 4,0000 4,0000 Time ml ml ml  5  98,5106,1 102,3 10 124,7 126,3 125,5 20 143,3 141,8 142,5 40 150,3 143,7147,0

Comparative Study of Preservation for Various Bulks After Three Months

Assembly of the curves were collected on the same figure for a generalview of the results.

Results

Curve 1: After ageing of 3 months the CO₂ release has clearly increased.

Curve 2: CO₂ release similar during the first 10 minutes and a littlevariation at the end.

Curve 3: increase of the CO₂ release

Curve 4: CO₂ decrease. It is the only of the 5 products which hasreleased the lesser of CO₂ after 3 months

Curve 5: Increase of the CO₂ release

The first day CURVE 1 CURVE 2 CURVE 3 CURVE 4 CURVE 5. Reference Mono NaGlutamic Pyroglutamic Mono suppositories phosphate acid acid citrate NaTime ml ml ml ml ml  5 26,65 59,4 41,2 88,9  70,52 10 52,31 76   66,6107,16  96,99 20 77,31 93,3 88,5 122,58 120,97 40 92,93 99,6 96,7 132,51

After 3 months CURVE 1 CURVE 2 CURVE 3 CURVE 4 CURVE 5 Reference Mono NaGlutamic Pyroglutamic Mono Na suppositories phosphate acid acid citrateTime ml ml ml ml ml  5 40.2 57.7 64.2 52.5 102.3 10 92.2 78.1 92.6 95.4125.5 20 117.0 100.5 109.8 111.4 142.5 40 121.6 113.3 112.8 113.4 147.0

The FIG. 1/1 collects the obtained results. The symbol A defines thevalues on the first day of manufacturing. The symbol B defines thevalues after preservation of 3 months.

Conclusion

After a 3 months preservation period, the control results of CO₂ releaseshow a very clear increase for the formulations 1, 3 and 5.

This phenomenon may be explained by a come back to stable state of thesemi-synthetic glycerides showing a decrease of the crushing strengthwith as a consequence a better reactivity between the components in someformulas.

On the other hand, formulations 2 and 4 release after preservation, anamount of CO₂ about the same than after manufacture.

What is claimed is:
 1. A pharmaceutical composition for rectaladministration formed with an effervescent mixture of sodium bicarbonateand glutamic acid with at least one diluent adapted for rectaladministration.
 2. A composition of claim 1 in the form of asuppository.
 3. A composition of claim 1 in the form of rectal capsules.4. A pharmaceutical composition for rectal administration formed with aneffervescent mixture of sodium bicarbonate and pyroglutamic acid with atleast one diluent adapted for rectal administration.
 5. A composition ofclaim 4 containing about 0.700 g of sodium bicarbonate and 0.85 to 0.90g of pyroglutamic acid.
 6. A composition of claim 4 in the form of asuppository.
 7. A composition of claim 4 in the form of rectal capsules.8. A pharmaceutical composition for rectal administration formed withabout 0.700 g of sodium bicarbonate and 1.15 to 1.20 g of monosodiumphosphate with at least one diluent adapted for rectal administration.